FUNCTIONS AND TARGETS OF LET-7 MICRO RNAS
The present invention concerns methods and compositions for treating or assessing treatment of diseases related to mis-expression of genes or genetic pathways that can be modulated by let-7. Methods may include evaluating patients for genes or genetic pathways modulated by let-7, and/or using an expression profile to assess the condition of a patient or treating the patient with an appropriate miRNA.
1 . A method of modulating gene expression in a cell comprising administering to the cell an amount of an isolated nucleic acid comprising a let-7 nucleic acid sequence in an amount sufficient to modulate the expression of a gene modulated by a let-7 miRNA family member.
2 . The method of claim 1 , wherein the gene modulated comprises one or more gene identified in Table 2 and Table 3.
3 . (canceled)
4 . The method of claim 2 , wherein the gene modulated comprises one or more of ATRX, AURKA/STK6, AURKB/STK12, BRCA1, BRCA2, BUB1, BUB1B, BZRP, CCNA2, CCNB1, CCNE2, CCNG2, CDC2, CDC20, CDC23, CDC25A, CDC6, CDCA7, CDK2, CDK6, CDKN2B, CDT1, CEBPD, CKS1B, CSF1, EIF4E, EPHB2, ERBB3, FASN, FGFBP1, FGFR4, FH, GMNN, IGFBP, IL8, ITGA6, JUN, JUNB, LHFP, MCAM, MET, MVP, MXI1, MYBL1, MYBL2, NRAS, P8, PDCD4, PLK1, PRKCA, RASSF2, SIVA, SKP2, SMAD4, TACC3, TFDP1, TGFBR3, TNFSF10, or VIM
5 . The method of claim 4 , wherein the genes modulated are ATRX, AURKA/STK6, AURKB/STK12, BRCA1, BRCA2, BUB1, BUB1B, BZRP, CCNA2, CCNB1, CCNE2, CCNG2, CDC2, CDC20, CDC23, CDC25A, CDC6, CDCA7, CDK2, CDK6, CDKN2B, CDT1, CEBPD, CKS1B, CSF1, EIF4E, EPHB2, ERBB3, FASN, FGFBP1, FGFR4, FH, GMNN, IGFBP, IL8, ITGA6, JUN, JUNB, LHFP, MCAM, MET, MVP, MXI1, MYBL1, MYBL2, NRAS, P8, PDCD4, PLK1, PRKCA, RASSF2, SIVA, SKP2, SMAD4, TACC3, TFDP1, TGFBR3, TNFSF10, and VIM.
6 . The method of claim 1 , wherein the cell is in a subject having, suspected of having, or at risk of developing acute lymphocytic leukemia; acute myeloid leukemia; alpha thalassemia; angiosarcoma; astrocytoma; breast carcinoma; bladder carcinoma; Burkitt's lymphoma; cervical carcinoma; carcinoma of the head and neck; chronic lymphocytic leukemia; chronic myeloblastic leukemia; colorectal carcinoma; endometrial carcinoma; fibrosarcoma glioma; glioblastoma; glioblastoma multiforme; gastric carcinoma; gastrinoma; hepatoblastoma; hepatocellular carcinoma; Hodgkin lymphoma; Kaposi's sarcoma; larynx carcinoma; leukemia; lung carcinoma; leiomyoma; leiomyosarcoma; lipoma; melanoma; medulloblastoma; myeloid leukemia; mesothelioma; myxofibrosarcoma; multiple myeloma; neuroblastoma; non-Hodgkin lymphoma; non small cell lung carcinoma; ovarian carcinoma; esophageal carcinoma; oropharyngeal carcinoma; osteosarcoma; pancreatic carcinoma; papillary carcinoma; prostate carcinoma; promyelocytic leukemia; renal cell carcinoma; retinoblastoma; rhabdomyosarcoma; sporadic papillary renal carcinoma; squamous cell carcinoma of the head and neck; salivary gland tumor; small intestinal carcinoma; T-cell leukemia; thyroid carcinoma; or orurothelial carcinoma, wherein the modulation of one or more gene is sufficient for a therapeutic response.
7 . (canceled)
8 . The method of claim 1 , wherein the let-7 nucleic acid comprises at least one of hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-let-7g, hsa-let-71, or a segment thereof.
9 . The method of claim 1 , wherein the let-7 nucleic acid is an inhibitor of let-7 function.
10 . The method of claim 1 , wherein the cell is a cancer cell.
11 . The method of claim 10 , wherein the cancer cell is skin cancer, ovarian cancer, esophageal cancer, pancreatic cancer, prostate cancer, salivary gland cancer, small intestine cancer, thyroid cancer, or liver cancer cell.
12 . The method of claim 1 , wherein the isolated let-7 nucleic acid is a recombinant nucleic acid.
13 . The method of claim 12 , wherein the recombinant nucleic acid is RNA.
14 . The method of claim 12 , wherein the recombinant nucleic acid is DNA.
15 . The method of claim 14 , wherein the recombinant nucleic acid comprises a let-7 expression cassette.
16 . (canceled)
17 . The method of claim 1 , wherein the let-7 nucleic acid is a synthetic nucleic acid.
18 . The method of claim 1 , further comprising modulating a cellular pathway comprising administering to a cell an amount of an isolated nucleic acid comprising a let-7 nucleic acid sequence in an amount sufficient to modulate the expression of a cellular pathway described in Table 9 and Table 12.
19 - 29 . (canceled)
30 . A method of treating a patient with a pathological condition comprising the steps of:
(a) administering to the patient an amount of an isolated nucleic acid comprising a let-7 nucleic acid sequence in an amount sufficient to modulate the expression of a cellular pathway; and
(b) administering a second therapy, wherein the modulation of the cellular pathway sensitizes the patient to the second therapy.
31 . The method of claim 30 , wherein the cellular pathway is one or more pathway described in Table 9.
32 . The method of claim 30 , wherein the let-7 nucleic acid comprises at least one of hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-let-7g, hsa-let-71 or a segment thereof.
33 . The method of claim 30 , further comprising:
(a) determining an expression profile of one or more genes selected from Table 2, 3, and 13;
(b) assessing the sensitivity of the subject to therapy based on the expression profile;
(c) selecting a therapy based on the assessed sensitivity; and
(d) treating the subject using selected therapy.
34 . An expression profile indicative of let-7 status in a cell or tissue comprising expression assessment of one or more gene from Table 2, Table 3, Table 13.